Use of condensated (hetaryl-substituted) 1-benzal-3-pyrazol derivates for treating special diseases of the cardiovascular and the central nervous systems

ABSTRACT

The present invention relates to the new use of 1-benzyl-3-(substituted hetaryl)-fused pyrazole derivatives, some of which are known, of the general formula (I)                    
     in which R 1  to R 4  have the meaning indicated in the description, as medicaments, and to new active compounds, in particular to their use as vasodilators, if appropriate in combination with organic nitrates and NO donors and if appropriate in combination with compounds which inhibit the degradation of cGMP.

This is a 371 of PCT/EP97/05381 filed Oct. 1, 1997.

The present invention relates to the new use of 1-benzyl-3-(substitutedhetaryl)-fused pyrazole derivatives, some of which are known, asmedicaments, and to new active compounds, in particular to their use asvasodilators, if appropriate in combination with organic nitrates and NOdonors and if appropriate in combination with compounds which inhibitthe degradation of cGMP.

It is already known that 1-benzyl-3-(substituted hetaryl)-fused pyrazolederivatives inhibit stimulated platelet aggregation in vitro (cf. EP-667345 A1; C. -C. Wu et al., Br. J. Pharmacol. 1995; 116: 1973-1978; F. -N.Ko et al., Blood 1994; 84: 4226-4233; S. -U. Yu et al., Blood 1996, 87:3758-3767).

It has now surprisingly been found that 1-benzyl-3-(substitutedhetaryl)-fused pyrazole derivatives of the general formula (I)

in which

R¹ represents hydrogen, halogen, hydroxyl or C₁-C₃-alkyl orC₁-C₃-alkoxy,

R² represents a radical of the formula

 in which

R⁵ denotes hydrogen, halogen, carboxyl, C₁-C₃-alkyl, C₁-C₃-alkoxycarbonyl or a radical of the formula —CH₂—OR⁶,

in which

R⁶ denotes hydrogen or C₁-C₃-alkyl,

R³ and R⁴ together form a radical of the formula

 in which

R⁷ denotes hydrogen, halogen, hydroxyl, C₁-C₃-alkyl or C₁-C₃-alkoxy,

and their isomeric forms and salts,

besides their weak antiaggregatory properties exhibit a markedvasodilatory action, in particular a lowering of blood pressure. Theyare thus suitable for the treatment of specific disorders of thecardiovascular system, in particular for the treatment of various formsof angina pectoris, of myocardial infarct, of cardiac insufficiency, ofarteriosclerosis, stroke and of hypertension.

The compounds of the general formula (I) according to the invention canalso be present in the form of their salts. In general, salts withorganic or inorganic bases or acids may be mentioned here.

In the context of the present invention, physiologically acceptablesalts are preferred. Physiologically acceptable salts can be salts ofthe substances according to the invention with mineral acids, carboxylicacids or sulphonic acids. Particularly preferred salts are, for example,those with hydrochloric acid, hydrobromic acid, sulphuric acid,phosphoric acid, methanesulphonic acid, ethanesulphonic acid,toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonicacid, acetic acid, propionic acid, lactic acid, tartaric acid, citricacid, fumaric acid, maleic acid or benzoic acid.

Physiologically acceptable salts can likewise be metal or ammonium saltsof the compounds according to the invention if they have a free carboxylgroup. Particularly preferred salts are, for example, sodium, potassium,magnesium or calcium salts, and also ammonium salts which are derivedfrom ammonia, or organic amines such as, for example, ethylamine, di- ortriethylamine, di- or triethanolamine, dicyclohexylamine,dimethylaminoethanol, arginine, lysine or ethylenediamine.

In the context of the invention, C₁-C₃-alkyl represents a straight-chainor branched hydrocarbon radical having 1 to 3 carbon atoms. Exampleswhich may be mentioned are: methyl, ethyl, propyl and isopropyl.

In the context of the invention, C₁-C₃-alkoxy represents astraight-chain or branched alkoxy radical having 1 to 3 carbon atoms.Examples which may be mentioned are: methoxy, ethoxy, propoxy andisopropoxy.

In the context of the invention, C₁-C₃-alkoxycarbonyl represents astraight-chain or branched alkoxycarbonyl radical having 1 to 3 carbonatoms. Examples which may be mentioned are: methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl and isopropoxycarbonyl.

Preferably, compounds of the general formula (I) according to theinvention

in which

R¹ represents hydrogen, fluorine, chlorine, C₁-C₃-alkyl or C₁-C₃-alkoxy,

R² represents a radical of the formula

 in which

R⁵ denotes hydrogen, chlorine, carboxyl, C₁-C₃-alkyl,C₁-C₃-alkoxycarbonyl or a radical of the formula —CH₂—OR⁶,

in which

R⁶ denotes hydrogen or methyl,

R³ and R⁴ together form a radical of the formula

 in which

R⁷ denotes hydrogen, fluorine, chlorine, C₁-C₃-alkyl or C₁-C₃-alkoxy,and their isomeric forms and salts,

are used for the treatment of specific cardiovascular disorders.

Particularly preferably, compounds of the general formula (I) accordingto the invention

in which

R¹ represents hydrogen, fluorine, chlorine or methoxy,

R² represents a radical of the formula

 in which

R⁵ denotes hydrogen, C₁-C₃-alkyl or a radical of the formula —CH₂—OR⁶,

in which

R⁶ denotes hydrogen or methyl,

R³ and R⁴ together form a radical of the formula

 in which

R⁷ denotes hydrogen, chlorine, fluorine, methyl or methoxy, and theirisomeric forms and salts,

are used for the treatment of specific cardiovascular disorders.

The invention additionally relates to new substances which are listed inthe following table:

TABLE

The known and new compounds of the general formula (I) according to theinvention can be prepared by customary methods, e.g. according to EP-667345 A1.

Moreover, the invention preferably also includes the combination of thecompounds of the general formula (I) according to the invention and ofthe new substances with organic nitrates and NO donors.

Organic nitrates and NO donors in the context of the invention are ingeneral substances which display their therapeutic action via therelease of NO or NO species. Sodium nitroprusside (SNP), nitroglycerine,isosorbide dinitrate, isosorbide mononitrate, molsidomine and SIN-1 andsimilar substances are preferred.

The invention additionally includes the combination with compounds whichinhibit the degradation of cyclic guanosine monophosphate (cGMP). Theseare in particular inhibitors of the phosphodiesterases 1, 2 and 5;nomenclature according to Beavo and Reifsnyder (1990) TIPS 11 pp.150-155. By means of these inhibitors, the action of the compoundsaccording to the invention is potentiated and the desiredpharmacological effect is increased.

The new and known compounds of the general formula (I) to be usedaccording to the invention exhibit an unforeseeable, valuable spectrumof pharmacological action. They induce, for example, a vasorelaxationand lead to a lowering of blood pressure and increase in the coronaryblood flow.

They are thus suitable for use in the treatment of specific disorders ofthe cardiovascular system such as, for example, the various forms ofangina pectoris, of myocardial infarct, of cardiac insufficiency, ofarteriosclerosis, stroke and of hypertension.

To determine the cardiovascular action, the following investigationswere carried out: in in vitro investigations on cells of vascularorigin, the influence on guanylate cyclase-dependent cGMP formation wastested with and without NO donors. The vasorelaxant action wasdetermined on rabbit aorta rings precontracted with phenylephrine. Thehypotensive action was investigated in anaesthetized rats.

Stimulation of Soluble Guanylate Cyclase in Primary Endothelial Cells

Primary endothelial cells were isolated from pig aortas by treatmentwith collagenase soln. The cells were then cultured in culture mediumuntil confluence was achieved. For the investigations, the cells werepassaged, inoculated into cell culture plates and subcultured untilconfluence was achieved. To stimulate the endothelial guanylate cyclase,the culture medium was aspirated and the cells were washed once withRinger's solution and incubated in stimulation buffer with or without NOdonor (sodium nitroprusside, SNP, 1 μM). Following this, the testsubstances (final concentration 1 μM) were then pipetted onto the cells.After the end of the incubation time of 10 minutes, the buffer solutionwas aspirated and the cells were lysed at −20° C. for 16 hours. Theintracellular cGMP was then determined radioimmunologically.

TABLE A Ex No. % cGMP increase (NOSYNTH)  1 >1000    2 72  3 250   4413   7 734   8 28 10 238  11 14 14 (YC-1) >906  EP 667 345 Al

Vasorelaxant Action in vitro

1.5 mm wide rings of an isolated rabbit aorta are placed individuallyunder a pretension into 5 ml organ baths containing carbogen-aeratedKrebs-Henseleit solution at a temperature of 37° C. The contractileforce is amplified and digitalized, and recorded in parallel on a linearrecorder. To generate a contraction, phenylephrine is added to the bathcumulatively in increasing concentration.

After several control cycles, the substance to be investigated isinvestigated in each further passage in increasing dose in each case andthe contraction is compared with the height of the contraction achievedin the last previous passage. From this, the concentration is calculatedwhich is necessary to reduce the height of the control value by 50%(IC₅₀). The standard administration volume is 5 μl.

TABLE B Ex. No. Aorta IC 50 (μM)  1 4.1  3 16  4 9.2 14 (YC-1) 10 EP 667345 A

Blood Pressure Measurements on Anaesthetized Rats

Male Wistar rats having a body weight of 300-350 g are anaesthetizedwith thiopental (100 mg/kg i.p.). After tracheotomy, a catheter isinserted in the femoral artery for blood pressure measurement. Thesubstances to be tested are administered orally in various doses as asuspension in Tylose solution by means of stomach tube.

TABLE C Ex. No. Dose Max. blood pressure decrease Time  1 10 mg/kg −14mm Hg 60 min 30 mg/kg −18 mm Hg 60 min 14 (YC-1) 10 mg/kg −10 mm Hg 60min EP 667 345 Al 30 mg/kg −18 mm Hg 60 min

The compounds described in the present invention are also activecompounds for the control of illnesses in the central nervous systemwhich are characterized by disorders of the NO/cGMP system. Inparticular, they are suitable for the elimination of cognitive deficits,for the improvement of learning and memory disorders and for thetreatment of Alzheimer's disease. They are also suitable for thetreatment of disorders of the central nervous system such as anxiety,tension and depressive states, sexual dysfunctions and sleep disorderscaused by the central nervous system, and for the regulation ofpathological disorders in food, semi-luxury food and addictive drugintake.

Furthermore, these active compounds are also suitable for the regulationof the cerebral circulation and are thus effective agents for thecontrol of migraine.

They are also suitable for the prophylaxis and control of the sequelaeof cerebral infarcts (cerebral apoplexy) such as stroke, cerebralischaemias and of cranio-cerebral trauma. The compounds according to theinvention can likewise be employed for the control of states of pain.

The present invention includes pharmaceutical preparations which,besides non-toxic, inert pharmaceutically suitable excipients, containone or more compounds according to the invention or which consist of oneor more active compounds according to the invention, and processes forthe production of these preparations.

The active compound(s) can optionally also be present inmicroencapsulated form in one or more of the excipients indicated above.

The therapeutically active compounds should be present in theabovementioned pharmaceutical preparations in a concentration ofapproximately 0.1 to 99.5, preferably of approximately 0.5 to 95% byweight of the total mixture.

Apart from the compounds according to the invention, the pharmaceuticalpreparations mentioned above can also contain further pharmaceuticalactive compounds.

In general, it has proved advantageous both in human and in veterinarymedicine to administer the active compound(s) according to the inventionin total amounts of approximately 0.5 to approximately 500, preferably 5to 100, mg/kg of body weight every 24 hours, if appropriate in the formof several individual doses, to achieve the desired results. Anindividual dose contains the active compound(s) according to theinvention preferably in amounts of approximately I to approximately 80,in particular 3 to 30, mg/kg of body weight.

PREPARATION EXAMPLES Example 1

1-(2-Fluorobenzyl)-3-(5 -hydroxymethylfuran-2-yl)-indazole

0.8 g(2.5 mmol) of 1-(2-fluorobenzyl)-3-(5-formyl-2-furanyl)-indazole issuspended in 40 ml of propanol and 0.8 g of NaBH₄ is added slowly at 0°C. After stirring at room temperature for 1 hour, the clear solution isadded to water, the mixture is extracted with ethyl acetate, the organicphase is dried with sodium sulphate and evaporated in vacuo, and theresidue is chromatographed on silica gel using, toluene/ethyl acetatemixtures as eluent.

620 mg (77% of theory) of crystals are obtained.

M.p. (melting point): 83° C.

R_(f) (SiO₂, toluene/ethyl acetate 2:1): 0.50

The examples in Tables 1, 2 and 3 were prepared analogously:

TABLE 1 Ex. M.p. ¹⁾ No. Structure ° C. 2

95 3

82 ¹⁾ Melting point

TABLE 2

Ex. Yield (% of theory) R_(f) No. R⁸ R⁹ M.p. ° C. 4

H  43 112 0.50 (TEA 1:1) 5

H  50 109 6

H  6 7

F  65 8

F  40  95 9

F  9

TABLE 3 Ex. Yield (% of theory) R_(f) No. Structure M.p. ° C. 10

 92  63 0.40 (H:EA 3 1) 11

12

 89 136 0.33 (H:EA 1:1) 13

 83 141 0.44 (H:EA 1:1) 14

112 YC-1 (EP 667345A1)

What is claimed is:
 1. A compound selected from the group consisting of:1-(2-fluorobenzyl)-3-(5-hydroxymethylfuran-2-yl)-indazole,1-(4-fluorobenzyl)-3-(5-hydroxymethylfuran-2-yl)-indazole,3-(5-hydroxymethylfuran-2-yl)-1-(3-methoxybenzyl)-indazole,1-(3-fluorobenzyl)-3-(5-hydroxymethylfuran-2-yl)-indazole,3-(5-hydroxymethylfuran-2-yl)-1-(2-methoxybenzyl)-indazole,1-(3-chlorobenzyl)-3-(5-hydroxymethylfuran-2-yl)-indazole,6-fluoro-1-(2-fluorobenzyl)-3-(5-hydroxymethylfuran-2-yl)-indazole,6-fluoro-3-(5-hydroxymethylfuran-2-yl)-1-(3-methoxybenzyl)-indazole,1-(3-chlorobenzyl)-6-fluoro-3-(5-hydroxymethylfuran-2-yl)-indazole,1-benzyl-3-(5-methylfuran-2-yl)-indazole,1-benzyl-3-(5-hydroxymethylthiene-2-yl)-indazole,4-fluoro-1-(2-fluorobenzyl)-3-(5-hydroxymethylfuran-2-yl)-indazole and5-fluoro-1-(2-fluorobenzyl)-3-(5-hydroxymethylfuran-2-yl)-indazole.
 2. Apharmaceutical composition comprising at least one compound according toclaim 1, or an isomer or a salt thereof and a pharmaceuticallyacceptable carrier.
 3. A process of preparing the pharmaceuticalcomposition according to claim 2 comprising combining said at least onecompound or an isomer or a salt thereof and a pharmaceuticallyacceptable carrier.
 4. Method for treatment of a cardiovasculardisorder, said method comprising administering to a patient in needthereof an effective amount therefor of at least one compound accordingto claim 1 or an isomer or a salt thereof.
 5. The method according toclaim 4 wherein said cardiovascular disease is hypertension.
 6. Methodfor treatment of a central nervous system disorder, said methodcomprising administering to a patient in need thereof an effectiveamount therefor of at least one compound according to claim 1 or anisomer or a salt thereof.
 7. A pharmaceutical composition comprising atleast one 1-benzyl-3-(subsitituted hetaryl)-fused pyrazole derivative ofthe general formula (I)

in which R¹ represents hydrogen, halogen, hydroxyl or C₁-C₃-alkyl orC₁-C₃-alkoxy, R² represents a radical of the formula

 in which R⁵ denotes hydrogen, halogen, carboxyl, C₁-C₃-alkyl,C₁-C₃-alkoxy carbonyl or a radical of the formula —CH₂—OR⁶, in which R⁶denotes hydrogen or C₁-C₃-alkyl, R³ and R⁴ together form a radical ofthe formula

 in which R₇ denotes hydrogen, halogen, hydroxyl, C₁-C₃-alkyl orC₁-C₃alkoxy, or an isomer or a salt thereof, organic nitrates and NOdonors.
 8. A pharmaceutical composition comprising at least one1-benzyl-3-(subsitituted hetaryl)-fused pyrazole derivative of thegeneral formula (I)

in which R¹ represents hydrogen, halogen, hydroxyl or C₁-C₃-alkyl orC₁-C₃-alkoxy, R² represents a radical of the formula

 in which R⁵ denotes hydrogen, halogen, carboxyl, C₁-C₃-alkyl,C₁-C₃-alkoxy carbonyl or a radical of the formula —CH₂—OR⁶, in which R⁶denotes hydrogen or C₁-C₃-alkyl, R³ and R⁴ together form a radical ofthe formula

 in which R₇ denotes hydrogen, halogen, hydroxyl, C₁-C₃-alkyl orC₁-C₃alkoxy, or an isomer or a salt thereof and compounds which inhibitthe degradation of cGMP.
 9. A process of preparing the pharmaceuticalcomposition according to claim 7 comprising combining said at least one1-benzyl-3-(subsitituted hetaryl)-fused pyrazole derivative, organicnitrates and NO donors.
 10. A process of preparing the pharmaceuticalcomposition according to claim 8 comprising combining said at least one1-benzyl-3-(subsitituted hetaryl)-fused pyrazole derivative andcompounds which inhibit the degradation of cGMP and a pharmaceuticallyacceptable carrier.
 11. Method for treatment of a cardiovasculardisorder, said method comprising administering to a patient in needthereof an effective amount therefor of at least one1-benzyl-3-(subsitituted hetaryl)-fused pyrazole derivative of thegeneral formula (I)

in which R¹ represents hydrogen, halogen, hydroxyl or C₁-C₃-alkyl orC₁-C₃-alkoxy, R² represents a radical of the formula

 in which R⁵ denotes hydrogen, halogen, carboxyl, C₁-C₃-alkyl,C₁-C₃-alkoxy carbonyl or a radical of the formula —CH₂—OR⁶, in which R⁶denotes hydrogen or C₁-C₃-alkyl, R³ and R⁴ together form a radical ofthe formula

 in which R₇ denotes hydrogen, halogen, hydroxyl, C₁-C₃-alkyl orC₁-C₃alkoxy, or an isomer or a salt thereof.
 12. The method according toclaim 11 wherein said cardiovascular disease is hypertension.
 13. Methodfor treatment of a central nervous system disorder, said methodcomprising administering to a patient in need thereof an effectiveamount therefor of at least one 1-benzyl-3-(subsitituted hetaryl)-fusedpyrazole derivative of the general formula (I)

in which R¹ represents hydrogen, halogen, hydroxyl or C₁-C₃-alkyl orC₁-C₃-alkoxy, R² represents a radical of the formula

 in which R⁵ denotes hydrogen, halogen, carboxyl, C₁-C₃-alkyl,C₁-C₃-alkoxy carbonyl or a radical of the formula —CH₂—OR⁶, in which R⁶denotes hydrogen or C₁-C₃-alkyl, R³ and R⁴ together form a radical ofthe formula

 in which R₇ denotes hydrogen, halogen, hydroxyl, C₁-C₃-alkyl orC₁-C₃alkoxy, or an isomer or a salt thereof.
 14. The method according toclaim 13 wherein said central nervous system disorder is a cerebralinfarct.